Background: Neoadjuvant PD-1 inhibitor plus chemotherapy in resectable non-small cell lung cancer (NSCLC) has become a standard of care. hypofractioned radiotherapy (HFRT) served as an immunomodulator and enhanced the effect of preoperative immunotherapy. In this phase Ib study, we evaluated the safety and feasibility of neoadjuvant HFRT with pembrolizumab plus chemotherapy in patients with potentially resectable stage III NSCLC. Methods: Patients with potentially resectable stage III NSCLC with EGFR/ALK wild-type were recruited to receive HFRT to the primary tumor followed by two cycles of pembrolizumab (100 mg/body) plus platinum-based doublet chemotherapy (Q3W). HFRT was delivered using 3 daily fractions, with a dose of 24 Gy for peripheral lesions and 12 Gy for central lesions. Central lesion is defined as a 2 cm area around the pulmonary artery and main bronchus. The decision for surgery was made through multidisciplinary team (MDT) discussion within a 4–6-week period after the completion of neoadjuvant treatment. Patients underwent surgery followed by adjuvant pembrolizumab for 2 years. Primary endpoint was safety. Secondary endpoints were efficacy, such as pathological complete response (pCR), progression-free survival (PFS), and overall survival (OS). Results: Between April 2021 and November 2023, 17 patients were enrolled with a median age of 66 years (range 54-74) and 15 (88.2%) having squamous cell lung cancer. 12 (70.6%) patients had stage IIIB disease, and 10 (58.8%) had central primary lesion. PD-L1 was ≥1% in 9 patients (52.9%). All patients received HFRT and at least one cycle of immunochemotherapy. No grade 3 or high adverse events were observed during neoadjuvant therapy. Only one patient had grade 1 nephrotoxicity, and another patient had grade 2 pneumonitis. A partial response was achieved in 16 out of 17 patients (94.1%), while one patient had stable disease after neoadjuvant therapy. Following MDT discussion, 11 patients (64.7%) met the surgical standards, while the remaining 6 patients were transitioned to definitive chemoradiotherapy. Among the 11 patients who underwent surgery, 8 (72.7%) achieved R0 resection, and 6 patients (54.5%) attained pCR. Only one patient died from intraoperative bleeding, and the remaining patients were followed up. The median PFS was 21.7 months, median OS were not reached, and the 2-year OS rate was 85.6%. The study was terminated early due to slow recruitment. Conclusions: Neoadjuvant HFRT with immunotherapy for potentially resectable stage III NSCLC is a tolerable treatment with an improved surgical conversion rate and pCR rate. Clinical trial information: ChiCTR2100045361.